Polymorphism is the ability of a substance to exist in two or more crystalline forms that have a different arrangement and/or conformation of molecules in a crystalline lattice (see e.g., Chawla and Bansal, CRIPS 2004, 5(1):9-12; Bernstein, “Polymorphism in Molecular Crystals,” IUCR Monographs on Crystallography 14, Oxford Science Publications, 2002, pp. 1-28, 240-256). It has been estimated that a large number of pharmaceuticals exhibit polymorphism. For example, 70% of barbiturates, 60% of sulfonamides, and 23% of steroids are believed to exist in different polymorphic forms or “polymorphs” (Haleblian et al., J Pharm Sci 1975, 64:1269-1288).
In some cases, when crystals of a compound are forming (e.g., crystallizing from a solution), solvent molecules may become entrapped or bound within the crystal lattice. The presence of the entrapped solvent molecules may affect the three-dimensional crystal lattice that eventually crystallizes. The occurrence of a compound (target molecule) crystallizing in different three-dimensional lattices based upon the presence of solvent molecules has been termed “pseudo-polymorphism.” Akin to polymorphs, such “pseudo-polymorphs,” also known as “solvates” (or “hydrates” when the solvent is water), are crystalline solids containing either stoichiometric (i.e., whole number ratios of target molecules to solvent molecules) or non-stoichiometric (i.e., non-whole number ratios of target molecules to solvent molecules) amounts of a solvent incorporated within the crystal structure. In general, different crystalline forms of molecules (e.g., pharmaceutical compounds) can exist in the same or different hydrated or solvated states.
The Cambridge Structural Database (Allen, “The Cambridge Structural Database: a quarter of a million crystal structures and rising,” Acta Crystallographica, 2002, B58, 380-388) is a database of over 300,000 organic crystal structures and is a widely used reference source in crystallography. One survey of the Cambridge Structural Database shows that pharmaceutical compounds have been reported to exist as hemi-hydrates (0.5 water molecules) through decahydrates (10 water molecules). (Morris, “Structural Aspect of Hydrates and Solvates,” Ch. 4 in Polymorphism in Pharmaceutical Solids, in Brittain, H. G., Ed., Vol. 95 of Drugs and the Pharmaceutical Sciences, Marcel Dekker, Inc., New York, N.Y., 1999, 125-181.)
The possibility of polymorphism or pseudo-polymorphism may exist for any particular compound, but the conditions required to prepare as yet unknown polymorphs or pseudo-polymorphs are not easily determined (see e.g., Bernstein, “Crystal Structure Prediction and Polymorphism,” Am Crystallographic Assoc Trans, 2004, 39:14-23). The knowledge that one type of polymorph or pseudo-polymorph of a crystalline form of a compound exists, or that a given set of crystallization conditions leads to the production of one type of polymorph or pseudo-polymorph, does not typically allow researchers to predict what other types of polymorph or pseudo-polymorph might exist, or what type of polymorph or pseudo-polymorph would be produced by other crystallization conditions (Guillory, “Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids,” Ch. 5 in Polymorphism in Pharmaceutical Solids, Brittain, H. G., Ed., Vol. 95 of Drugs and the Pharmaceutical Sciences, Marcel Dekker, Inc., New York, N.Y., 1999, pp. 183-226).
The existence of various polymorphs or pseudo-polymorphs can greatly affect a pharmaceutical's performance since each form can have different physical and chemical properties. For example, one particular polymorph pseudo-polymorph may be more bioavailable, more stable (e.g., longer shelf life), or more easily formulated or tableted than another polymorph. Similarly, one polymorph pseudo-polymorph may be more active or less toxic than another. Some specific examples of the dramatic difference that can exist between various pharmaceutical polymorphs are described in, e.g., Brittain et aL, J Pharm Sci 2002, 91:1573-1580 and Morissette et al., Proc Natl Acad Sci USA 2003, 100:2180-2184.
The effects of polymorphism and pseudo-polymorphism on quality and performance of a drug is widely recognized. The exact solid state polymorph (or pseudo-polymorph) of a compound determines its physical properties such as dissolution rate, solubility, bioavailability, crystal habit, mechanical strength, etc. (Datta et al., Nature Reviews-Drug Discovery, 2004, 3:42-57). The delivery of an exact dosage in manufacture and the manufacturing process itself often depend on which of several possible polymorphs or pseudo-polymorphs are present.
The variation in properties among different polymorphs (or pseudo-polymorphs) usually means that one crystalline form is desired or preferred over other forms. Obtaining a particular form can be difficult, however. Typically, researchers have to experiment with a multitude of variables in crystallization conditions, such as aqueous solvent mixtures, amount of water, amount of target compound, relative humidity, temperature of incubation, incubation time, etc., in a process characterized by trial and error. Further, the search for salts of crystalline forms (usually sought after to control dissolution rate and solubility) can require extensive experimentation. Each salt of a drug or each different solvent used to crystallize the drug or a salt of the drug may lead to polymorphs or pseudo-polymorphs that have to be fully investigated and that have different properties (see e.g., Reutzel-Edens et al., “Anhydrates and hydrates of olanzapine: Crystallization, solid-state characterization, and structural relationships,” Crystal Growth & Design, 2003, 3:897-907).
Moreover, the inadvertent production of an undesired polymorph (or pseudo-polymorph), or the spontaneous transformation from the desired crystalline form to an undesired form, can result in crystalline forms of a drug that are less effective or even toxic. Thus, the existence and control of polymorphism and pseudo-polymorphism can be the biggest challenge to obtaining a drug product of constant quality.
Another important issue regarding polymorphism and pseudo-polymorphism is that there can be considerable regulatory hurdles for a drug that exists in various crystalline forms. The FDA's regulatory guidelines emphasize control of crystal form and the use of appropriate techniques to detect and characterize different forms of a drug (see Guidance for Industry ANDAs: Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, and Controls Information, U.S. Department of Health and Human Services, FDA, 2004). Thus, an applicant seeking FDA approval of a drug must demonstrate the ability to maintain a constant crystalline form throughout the life of the product. Such an endeavor is costly and can be extremely difficult or even impossible.
Similar challenges can exist when one seeks approval of a generic product by filing an Abbreviated New Drug Application (ANDA), in which case the applicant must show equivalence between the generic drug and an approved drug. Such a showing can be complicated when various polymorphic and/or pseudo-polymorphic forms exist for the drug.
Amorphous forms of drugs are now being studied because they are higher energy forms that have higher dissolution rates and solubilities since there is no lattice structure to overcome or to inhibit solvation (Bernstein, “Polymorphism in Molecular Crystals,” IUCR Monographs on Crystallography 14, Oxford Science Publications, 2002, pp. 240-256). This increasing attention to amorphous forms has also shown, however, that the amorphous forms have a tendency to crystallize spontaneously to a lower energy crystalline form, usually at inopportune times.
The phenomenon of polymorphism and pseudo-polymorphism is not limited to pharmaceuticals as many other (if not all) organic and inorganic compounds can crystallize into different forms. Thus, the existence of various forms of a given compound (e.g., a pesticide, herbicide, nutraceutical, cosmetic, food additive, explosive, etc.) can result in the same synthetic, analytical, regulatory, and commercial difficulties that plague the pharmaceutical industry because of polymorphic and pseudo-polymorphic drugs. In each of these industries, it is not currently possible to simply alter the chemical nature of the active compound in order to tune the chemical (e.g., rate of dissolution and solubility) or physical (crystal habit, mechanical strength) properties. Rather, it is often the strategy to search for polymorphs or pseudo-polymorphs that have the most desirable “obtainable” properties.
Another common problem that exists with many pharmaceuticals is low solubility. Low solubility can make formulating a particular compound difficult, and generally low solubility translates into low bioavailability. Much research is conducted on finding ways to improve a compound's solubility and availability. Typically methods include complex delivery devices and chemical modifications of the drug.
Given that polymorphism and pseudo-polymorphism cannot be predicted; that the exact crystalline state affects chemical properties (e.g., dissolution rate, solubility), biological properties (e.g., bioavailability, pharmacokinetics), mechanical and physical properties, and manufacturing processes, and that polymorphs and pseudo-polymorphs can inconveniently interconvert, what are needed are compositions that are at least effective for their intended purpose, but can also have controlled and tunable chemical, biological, and physical properties, are in a form that is not subject to polymorphism, and for which controlled, tunable dissolution and solubility are possible. Methods of preparing and using such compositions are also needed. Further methods of converting a compound that is difficult to solubilize into a more soluble form are also desired. The compositions and methods disclosed herein meet these and other needs including the introduction of enhanced or new functionality.